CORE 1: BIOMEDICAL COMPUTATION RESEARCH The mission of Simbios is to develop, disseminate, and support a simulation tool kit (SIMTK) that enables biomedical scientists to develop and share accurate models and simulations of biological structuresfrom molecules to organisms. We have developed, tested, and released SIMTK version 2.0, which includes high performance algorithms for performing matrix operations, generating and integrating equations of motion, performing linear and nonlinear optimization, modeling contact between bodies, and calculating molecular interaction forces (Figure ES.2). SIMTK has enabled the development of powerful graphics-based applications. For example, OPENSIM, built from SIMTK, is focused on simulation of human biomechanics, using LAPACK for linear algebra, SIMBODY for multibody dynamics, IPOPT for optimization, and other SIMTK components. OPENMM ZEPHYR, an easy-to-use interface for atomistic molecular dynamics, builds on SIMTK using GPU-accelerated molecular force field calculations. RNABUILDER simulates coarse-grained models of large complexes of RNAs and proteins, making extensive use of LAPACK, SIMBODY and other SIMTK components. Through SIMTK, and the applications that use it, we have enabled thousands of researchers to do rigorous, high-performance physics-based simulations. SIMTK has been developed and tested in close collaboration with hundreds of biomedical scientists to ensure its accuracy and utility. Our past driving biological problems (DBPs) have included research projects in RNA folding, protein folding, myosin dynamics, cardiovascular mechanics, and neuromuscular biomechanics. By choosing DBPs that represent important areas of research, our software innovations find broad applications. SIMTK version 2.0 contains two complementary systems: a sophisticated open source multibody mechanics code, SIMBODY, that forms the basis for modeling applications in biomechanics and molecular mechanics, and an interacting particle open source code, OPENMM, that provides extremely fast force-field computations for large numbers of interacting components. These codes are based on state-of-the-art research innovations, and are built and documented by experienced software engineering professionals, who have developed and delivered complex software packages to thousands of users. LEVERAGING A NEW GENERATION OF COMPUTER HARDWARE Physical simulation is one of the most computationally intensive activities in biocomputing, and therefore is highly dependent on advances in hardware technology. Recently, there has been a shift in hardware towards complex heterogeneous multicore architectures. This is not simply computing with graphics cards, but a much more fundamental shift in how Moore's law of computing power will advance: clock rates have stopped improving but the transistors continue to get smaller, and will be arranged in massively parallel arrays on special purpose hardware. We will take the lead in ensuring that biophysical simulation develops appropriately to use these new architectures, and have engaged in a collaboration with the Stanford Pervasive Parallelism Lab (PPL) to design domain specific languages (DSLs) that will provide an application programmer interface that hides the complexity of programming these complex new architectures.